Parkinson's disease (PD) is clinically characterized by bradykinesia, rigidity, tremor, and gait disturbance that progresses slowly over many years. The pathophysiological loss of dopamine neurons is a hallmark of this disorder and has guided treatments for reducing symptoms. Post mortem studies in PD demonstrate a marked reduction of dopamine neurons and the molecular targets located on terminals of dying neurons. These targets include the dopamine transporter (DAT) and vesicular monoamine transporters type 2 (VMAT 2). These two targets have been implicated in mediating the progression of the neurodegenerative process in PD. Neuroimaging techniques using positron emission tomography (PET) and single photon emission tomography (SPECT) have been useful in better characterizing the disease process in vivo in PD using these markers of dopamine cell loss. One presynaptic cell marker for VMAT 2 is l lc labeled tetrabenazine. This tracer has been used in a limited number of PD patients owing to the logistical difficulty in performing large-scale clinical evaluations. The widespread use and commercial application of the tracer is limited by the very short half-life of the l lc nuclide (20 rain) used to tag the chemical moiety. The wider use of this promising clinical and research tool will require a more practical radioisotope. In this application, we propose to develop a longer half-life (123I, half life 13 h) SPECT radiotracer for VMAT 2 imaging in PD patients. Our goal is to prepare a radioiodinated tetrabenazine analog. A simple radiochemical synthesis will be developed for this tracer. We will assess the in vitro properties of newly developed compounds. In addition, we will assess its biological properties in vivo using rodents that will include selectivity for the target site, penetrance in brain tissue, pharmacodynamic properties of the radioligand during pharmacological interventions in mice.